Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3
- Pereira Sena, P., Weber, J.J., Watchon, M., Robinson, K.J., Wassouf, Z., Hauser, S., Helm, J., Abeditashi, M., Schmidt, J., Hübener-Schmid, J., Schöls, L., Laird, A.S., Riess, O., Schmidt, T.
- Proceedings of the National Academy of Sciences of the United States of America 118(47): (Journal)
- Registered Authors
- Laird, Angela, Watchon, Maxinne
- Machado–Joseph disease, O-GlcNAc, OGT, Spinocerebellar ataxia type 3, ataxin-3
- MeSH Terms
- Disease Models, Animal
- HEK293 Cells
- Machado-Joseph Disease/metabolism*
- Machado-Joseph Disease/pathology*
- Proteasome Endopeptidase Complex
- 34785590 Full text @ Proc. Natl. Acad. Sci. USA
Pereira Sena, P., Weber, J.J., Watchon, M., Robinson, K.J., Wassouf, Z., Hauser, S., Helm, J., Abeditashi, M., Schmidt, J., Hübener-Schmid, J., Schöls, L., Laird, A.S., Riess, O., Schmidt, T. (2021) Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3. Proceedings of the National Academy of Sciences of the United States of America. 118(47):.
Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasome-dependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes